Once viewed undruggable, frequently mutated oncogene KRAS has led to the recent approval of two KRAS^G12C small molecule covalent inhibitors targeting the inactive GDP-bound (OFF) state. Patient benefit has fallen short with these first-generation inhibitors due to innate or acquired resistance driven by upregulation of the activated GTP-bound (ON) state of KRAS^G12C. We present the discovery of potent dual inhibitor FMC-376 targeting both active and inactive forms of KRAS^G12C.

Resistance is a limitation of all RAS inhibitors approved or in development. I will present the discovery of ADT-1004, a novel pan-RAS inhibitor with low potential for resistance and unique selectivity for RAS mutant cancer cells. ADT-1004 displayed robust antitumor activity in multiple mouse models of pancreatic cancer without discernable toxicity. Side-by-side comparison showed superior anticancer activity over FDA approved mutant-specific KRAS inhibitors, as well as pan-KRAS inhibitors and other pan-RAS inhibitors in clinical trials.

Casitas B lymphoma-b (CBL-B) is a RING-type E3 ubiquitin ligase that plays an important role in regulating T cell function. Loss of CBL-B is associated with enhanced T and NK cell activity which makes it an interesting target for immuno-oncology drug development. We present a rational approach to discover and optimize small molecule inhibitors for CBL-B that elicit a potent T cell activation and antitumor activity.

Knockout of the RING E3 ubiquitin ligase cbl-b causes tumor rejection in murine models and as such represents a promising target for cancer immunotherapy. We screened a DNA-encoded library and discovered a xanthene-containing lead molecule that bound to and inhibited cbl-b with affinity in the high nanomolar range. An x-ray co-crystal structure showed this lead molecule bound to the SH2 domain of cbl-b. Here we describe these studies in addition to a medicinal chemistry optimization effort that provided an inhibitor with measurable activity against cbl-b in cells.

Deubiquitinating enzymes (DUBs) are a class of ~100 cysteine proteases, of interest as emerging drug targets and for application in targeted protein stabilization. Pairing a bespoke library with activity-based protein profiling as a high-density primary screen, we identify and validate a multitude of promising chemical starting points and a direct path to tool compounds that can be used to decipher DUB function, substrates, and signaling pathways.

Inhibition of PLK1 may be key to overcoming resistance to androgen blocking treatments that result in Castration Resistant Prostate Cancer (CRPC) providing new therapeutic options. Using the REPLACE strategy, we found compounds that bind tightly to PLK1 and induce its degradation. Through our hit to lead conversion studies we identified an abbapolin with potent on target cellular engagement of PLK1, good oral pharmacokinetics and antitumor efficacy in prostate xenografts.

Despite recent advances in KRAS inhibitors for cancer therapy, a majority of KRAS alterations remain unaddressed. The rapid emergence of resistance where inhibitors are available underscores the need for novel approaches. We will discuss our focus on targeted protein degradation to eliminate mutant KRAS as a promising avenue for superior and durable efficacy.

Description:Bi-functional degraders occupy beyond-rule-of-five chemical space where established rules for drug-likeness cannot easily be applied. In contrast to approved CNS drugs, bi-functional degraders violate most metrics, particularly molecular weight, yet we routinely observe brain penetrance in our programs. For example, NX-5948, a clinical stage orally bioavailable BTK degrader shows CNS exposure and activity both preclinically and clinically. This presentation will explore our evolving understanding of targeting the CNS using degraders.

The zinc finger transcription factor Helios (IKZF2) is highly expressed in Tregs and plays an important role in helping tumors evade a normal immune response. IKZF2 is a transcription factor that had been considered "undruggable." Here we disclose the discovery and preclinical evaluation of a selective molecular glue degrader of IKZF2 (PLX-4545) which reverses Treg suppression and is currently being evaluated in a Phase 1 trial of healthy volunteers.

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

The chemistry strategy was established to enable targeted delivery of a cyclic dinucleotide STING agonist TAK-676 to CCR2+ myeloid cells through an antibody-drug conjugate approach. A self-immolative spacer between the adenine of TAK-676 and the cleavable dipeptide linker rendered a linker payload with enhanced plasma stability. Stochastic cysteine conjugation of the linkers provided immune cell-stimulating ADC TAK-500. In mouse models, mTAK-500 showed antitumor activity driven by immune cell activation.

Immunotherapy, a groundbreaking paradigm in cancer treatment, has achieved remarkable success, including the cure of metastatic diseases. However, many patients see no benefit as multiple resistance mechanisms can hinder the effectiveness of immunotherapy. Our innovative approach at Domain is powered by precision. We have developed a unique pipeline of GPCR targeting drug candidates, which aims to unlock new therapeutic possibilities in cancer. These candidates specifically target immunosuppressive mechanisms, enabling us to deliver innovative immunotherapies. In this presentation, we’ll delve into the identification of novel immunosuppressive GPCRs. Additionally, we’ll explore small molecule drug discovery approaches, emphasizing Domain’s approach of precision research.